1. Field of the Invention
The present invention relates generally to the field of pharmaceutical preparations and in particular to the field of oral contraceptives and hormone replacement therapy. In particular the present invention addresses the field of peak bone mass accrual in young oral contraceptive users and restoration of normal hormonal balance in women of any age in need thereof.
2. Description of the Related Art
Due to the relatively high rate of teenage pregnancy in the United States, pediatric and adolescent gynecologists often recommend that young women take some form of contraception to prevent unwanted pregnancies (The Contraception Report, 1995). The most common method of contraception among adolescents is oral contraceptives, taken by approximately 46% of the sexually active population. Consequently, almost half of all premenopausal women (&lt;44 years) are potentially taking oral contraceptives while their skeleton is still maturing and before reaching peak bone mass, which occurs at about age 30-35. Peak bone mass is a term that describes a point at which the maximum bone density is reached. For a woman, bone density increases until about age 30-35, and then slowly decreases for the remainder of her life. This peak is known as the peak bone mass. As the bone density decreases in later years, osteopenia and osteoporosis with bone fractures are more likely to occur. It is important, therefore, to forestall these problems by attaining as high a peak as possible.
Although estrogen is necessary for maintaining bone density in premenopausal women, the role of androgens or their combined effect is unclear. It is generally accepted that low-dose estrogens are potent bone growth promoters and probably provide the major growth stimulus in girls, while in boys, estrogens may be involved in the growth spurt along with testosterone (Kulin, 1991). However, some recent evidence suggests that androgens play an important role in building and maintaining bone in the female as well as in the male. During puberty, androgens influence bone growth and peak bone mass, but after puberty, during adolescence and early adulthood, androgens are also involved in the maintenance of bone mass. Peak bone mass is acquired by age 30-35 (Recker, et al., 1992), but 15% of the adult height and 48% of the skeletal mass are attained during adolescence.
Oral contraceptive treatment, like oophorectomy, causes a significant decrease in androgen levels and consequently oral contraceptives are commonly used to treat hirsutism in women (Carr, et al., 1995). Young women with hyperandrogenemia show increased levels of luteinizing hormone (LH) and free testosterone to total testosterone ratio (fT)/T, and a decreased serum level of sex hormone-binding globulin (SHBG). Low-dose oral contraceptives reduce the hormone imbalance and hyperandrogenemia (Yamamoto and Okada, 1994; Rosenfield and Lucky, 1993). Interestingly, not only does oral contraceptive therapy lower serum A, T and fT in hyperandrogenic women, but estradiol (E2) levels also significantly decrease with oral contraceptive therapy.
Among the first orally active steroids to be used in inhibiting ovulation, some had inherent estrogenic activity and some preparations of progestins were later found to be contaminated with estrogen. This suggested that estrogen enhanced the suppressive effect of the progestin and led to the general use of a mixture of the two. A comprehensive investigation of the inhibition of ovulation by the use of progestational agents was initiated by Rock, Pincus, and Garcia. The study showed that ovulation could be abolished at will for as long as desired and with great regularity (Rock et al, 1957; Pincus, 1960). The compounds used were derivatives of 19-nortestosterone, given by mouth from day 5 to day 25 of the menstrual cycle (the first day of menses is day 1).
The most common type of oral contraceptive is the combination preparation, which contains both an estrogen and a progestin. Experience with these preparations shows them to be 99 to 100% effective. This method of reversible contraception is, then , the most effective yet devised. Other modifications of steroidal contraception have also been tried with success. Sequential preparations, in which an estrogen is taken for 14 to 16 days and a combination of an estrogen and a progestin is then taken for 5 or 6 days, have been about 98 to 99% successful as oral contraceptives. However, because of reports suggesting an increased incidence of endometrial tumors and a lower efficacy, sequential preparations of this type have been removed from th e market. They have been replaced by products that contain estrogen and relatively low amounts of a progestin that varies during the monthly cycle. Biphasic and triphasic formulations of sequential preparations of oral contraceptives are listed in Table 1. These preparations have been developed in attempts to lower the total amounts of hormone given and thus to reduce the incidence and severity of side effects.
The relationship between oral contraceptive use and skeletal health ha s been examined in a number of human studies. Tuppurainen, et al. (1994) studied the effects of oral contraceptive use on BMD in perimenopausal women (48-60 years). Twenty-nine percent of the women were past users of or al contraceptives. Oral contraceptive users (n=939) had a slightly higher (but statistically significant) lumbar BMD than non-users (n=2283). The study with the largest number of subjects (the Oral Contraception Study of the Royal College of General Practitioners, n=46,000 women) was carried out between 1968 and 1990 and examined the relationship between oral contraceptive use and subsequent incidence of first fractures (excluding skull, rib, and multiple fractures) in married or living as married women (Cooper, et al., 1993). After adjustment for age, parity, cigarette smoking, and socioeconomic class, women who had ever used oral contraceptives were found to be at significantly higher risk for subsequent fractures (relative risk 1.20) compared to women who had never used oral contraceptives. Thus, this very large prospective study suggests that oral contraceptive use does not promote long term skeletal health and may even be detrimental in terms of fracture risk.
While the majority of studies in humans have utilized female populations with age ranges well into the postmenopausal years, a few studies have focused on "younger" females who have not yet attained peak bone mass. In a longitudinal study of 156 premenopausal women aged 20-30, Recker, et al. (1992) found a positive association between oral contraceptive use and whole body bone mass, but no association with lumbar spine (L2-L4) or forearm bone mass. Lindsay, et al. (1986) reported results from 2 cross-sectional studies, one of which involved 57 healthy premenopausal women between 25 and 35 years of age, 24 of which had previously taken oral contraceptives (30 or 50 mg ethinyl estradiol along with norgestrel) for more than 6 months. None of the subjects was taking oral contraceptives at the time of the study. Previous oral contraceptive use was associated with increased BMD in the lumbar spine but not in the radius. The second cross-sectional study showed no association between oral contraceptive use on lumbar spine BMD in 14 postmenopausal women compared to 24 age-matched controls.
In a cross-sectional study of 60 women aged 24-35, Kanders, et al. (1984) found that oral contraceptive users (greater than 5 months use) had a significantly higher spinal BMD than non-users. Goldsmith and Johnston (1975) examined the relationship between oral contraceptive use and distal radius bone mineral among different populations of women in a large cross-sectional study carried out in 1969 and 1970, when most of the oral contraceptive users aged 20-29 were taking mestranol (n=219) and relatively few were taking ethinyl estradiol (n=47). High dose mestranol use (&gt;100 mg/day) was associated with increased radial bone mass, while ethinyl estradiol (50 or 100 mg/day) use and radial bone mass were not associated in white women (n=65) and were negatively associated in black women (n=11).
Stevenson, et al (1989) found no association between oral contraceptive use and bone density at several sites, including lumbar spine, in 112 premenopausal women aged 21-52 (median age=34.1). However, positive associations were found between bone density at these same sites and oral contraceptive use in 172 postmenopausal women aged 28-68 (median age=53.4). Mazess and Barden (1991) found no relationship between oral contraceptive use and BMD of the spine, radius, or femoral neck in a study of 200-300 healthy women of 20-39 years of age. Recently, Hansen (1994) studied 249 healthy premenopausal women aged 21 to 51 (17 were &lt;30 years of age) and reported no association of oral contraceptive use with bone density at a number of skeletal sites, although a significant reduction (&lt;32%) in BGP was observed in current oral contraceptive users compared to never users.
In a recent study, young women using oral contraceptives did not gain spinal bone density over time (Carr, et al., 1995). According to their reported age (mean age of 26.+-.1 yr) and using regression lines reported by Recker, et al (1992), bone mass in most of the women in this study should have been increasing during the study period, ending with a positive balance. Also, Teegarden, et al. (1995), investigated the interaction between oral contraceptive use and exercise in women ages 18 to 31 years. Surprisingly, after 6 months, women who were exercising and using oral contraceptives lost a significant amount of spinal bone mineral density (BMD), whereas women not exercising and taking oral contraceptives gained a significant amount of spinal BMD. Serum concentrations of hormones were not reported (Teegarden, et al., 1995). These results suggest serious consequences. If young women who exercise and take oral contraceptives fail to gain bone during their adolescent and young adult years (ages 15 to 30 years), they will attain a lower than expected peak bone mass. Therefore, age-related and postmenopausal bone loss will have a greater effect on bone mass and a fracture threshold may be reached earlier in life.
Another area of need, in relation to hormonal therapies, is in the mature population of women who take estrogens, and/or progestins for birth control, and/or for hormone replacement therapy (HRT) for women undergoing menopause, or without functioning ovaries. This group would include premenopausal, perimenopausal and postmenopausal women. There is a need, for example, for a therapy that would prevent pregnancy in women undergoing menopause, that would also alleviate at least some of the symptoms of menopause. An added benefit of such a product would be an increase in the psychological well being, the libido, and sexual function in this population.
One effect of estrogen supplementation is an increase in sex hormone-binding globulin (SHBG) (Raisz et al., 1996), which has been reported to increase up to 200 to 240% in women given a combination of ethinyl estradiol and a progestin (Wiegratz et al., 1995). Sex hormone-binding globulin is a serum protein that binds both testosterone and 17.beta.-estradiol, a nd this binding affects the biological availability of those hormones. Therefore, the increase in SHBG, that occurs with estrogen and progestin supplementation results in lower levels of free androgens and estrogens, both of which bind to SHBG, and higher levels of estrogens have to be administered in order to achieve the desired biological activity. The ideal therapy would counteract th is SHBG effect so that the benefits of estrogen/progestin therapy could be achieved at lower hormone supplementation levels.
There is an immediate need therefore, for an oral contraceptive, especially for women in their teens and twenties, that is effective to prevent unwanted pregnancies and still allows the attainment of normal peak bone mass. There is also a need for a hormone replacement therapy regimen that counteracts the SHBG effect. Such a regimen would achieve the beneficial effects of estrogen therapy at lower estrogen levels, t hu s decreasing the probability of deleterious side effects such as thromboembolic disease and breast cancer.